利用酵母菌系統探討人類SDHD(Sdh4/Shh4)參與遺傳性副神經節瘤之機制

Abstract

Hereditary paraganglioma (PGL) is a rare tumor that is mostly benign and mainly arises in the head, neck and abdomen. The first gene shown to be directly linked to PGL syndrome was SDHD. 87–100% of SDHD mutation carriers develop tumors. However, the exact mechanism for tumorigenesis of PGL is elusive. SDHD encodes a subunit of the mitochondrial tricarboxylic acid cycle enzyme, succinate dehydrogenase (SDH), which is a complex II component of the electron transport chain. In yeast Saccharomyces cerevisiae, Sdh4 is an ortholog of hSDHD, which major performs the succinate dehydrogenase function in the Sdh complex. Here we discovered a yeast mitochondrial novel protein, Shh4/Ylr164w, which displays higher sequence conservation to hSDHD than Sdh4. The protein expression level of Shh4 is increased when cells enter aerobic respiration. In nonfermentable carbon source, deletion of SHH4 further decreases the growth of sdh4△ cells. Deletion of SHH4 further decreases the mitochondrial membrane potential of sdh4△ cells in stationary phase. Deletion of SDH4 upregulates SHH4 expression. Furthermore, SHH4 overexpression rescues the inviable phenotype of sdh4△ upon growth on a nonfermentable carbon source. Shh4 is associated with Sdh3 and deletion of SDH4 increases the interaction between Sdh3 and Shh4. We also investigated the mechanism of PGL tumorigenesis by using S. cerevisiae as a model organism. As our result showed, the level of reactive oxygen species (ROS) and mutation frequency were increased in the SDH4 and SHH4 double-deleted cells. Altogether; these results demonstrate that Shh4 is another subunit of succinate dehydrogenase in yeast. Our data suggest that the deficiency of hSDHD/Sdh4p/Shh4p may result in an increased production of ROS which contributes to an increase in mutation frequency, genome instability, and PGL tumorigenesis.